AN EVALUATION ON THE PRACTICE,

PERCEPTIONS AND KNOWLEDGE ON THE

USE OF ACETAMINOPHEN (PARACETAMOL)

AMONG THE LOCAL CONSUMERS IN

PENANG, MALAYSIA

TAN SEAK FANG

UNIVERSITI SAINS MALAYSIA

2016

AN EVALUATION ON THE PRACTICE,

PERCEPTIONS AND KNOWLEDGE ON THE

USE OF ACETAMINOPHEN (PARACETAMOL)

AMONG THE LOCAL CONSUMERS IN

PENANG, MALAYSIA

BY

TAN SEAK FANG

Thesis submitted in fulfilment of the requirements

for the Degree of

Master of Science (Clinical Pharmacy)

June 2016

ii

ACKNOWLEDGEMENTS

I wish to express my sincere thanks to all the people that has contributed to the

completion of this thesis.

Firstly, I would like to thank Universiti Sains Malaysia (USM) for giving me a chance

to further my master study in School of Pharmaceutical Sciences, USM.

Secondly, I would like to thank my main supervisor, Dr Chong Chee Ping. I am

grateful for his patient, guidance and sincere in helping in my study. He had taught me

to do research systematically and his willingness to share his profound knowledge

helped me a lot in my study.

Thirdly, I would like to thank my co-supervisor, Dr Chooi Weng Tink and Dr Idris bin

Mansor. I am appreciated for their fruitful guidance, comments and suggestions during

the study. They had encouraged me to overcome all obstacles that I faced during the

study.

Fourthly, I would like to thank the Institut Perubatan dan Pergigian Termaju USM

(IPPT) Out-Patient Clinic, USM Health Clinics and Lotus Pharmacy Sdn. Bhd. for

given me an opportunity to conduct my data collection in their institutions.

Besides, I cannot forget to thanks in advance Puan Ernest, a statistical advisor in IPPT

and Dr Ali bin Samsuddin, a senior lecturer in School of Educational Studies, USM.

They provided statistical advice and alternatives for the analysis in my research data.

I am also touched to their friendly support and enthusiasm. Many thanks to

Professional Development and Advisory Services Unit, Institute of Postgraduate

Studies, USM for organizing many workshops to enhance my statistical skills.

Finally, a special appreciation goes to my family members for their support and

concern throughout my education years.

iii

TABLE OF CONTENTS

Page

Acknowledgement

ii

Table of contents

iii

List of Tables

vi

List of Abbreviations

vii

List of Appendices

ix

Abstrak

x

Abstract xii

CHAPTER 1: GENERAL INTRODUCTION

1.1 Introduction 1

1.2 Problem statement 3

1.3 Rational for the study 4

1.4 General objectives 5

1.5 Specific objectives 5

1.6 Overview of the thesis 5

CHAPTER 2: LITERATURE REVIEW

2.1 The use of over-the-counter (OTC) medicinal products among the

consumers

7

2.2 The use of acetaminophen products among the consumers

7

2.3 Epidemiology of acetaminophen poisoning in overseas 9

2.4 Epidemiology of acetaminophen poisoning in Malaysia 10

2.5 Recommended dose of acetaminophen in adults and children 11

2.6 Toxic dose of acetaminophen in adults and children 11

2.7 Acetaminophen poisoning

2.7.1 Prognosis of acetaminophen poisoning 12

2.7.2 Risk factors of acetaminophen poisoning 13

2.7.3 Clinical presentations of acetaminophen poisoning 13

2.7.4 Acetaminophen induced hepatotoxicity and fulminant

hepatic failure (FHF)

15

2.7.5 Acetaminophen induced nephrotoxicity 16

2.7.6 King’s College Hospital (KCH) criteria for liver

transplantation in patient with FHF

16

2.7.7 Modified King’s College Hospital criteria for liver

transplantation in patient with FHF

17

2.7.8 Severe acute liver failure related to therapeutic use of

acetaminophen (SAF-M) versus severe acute liver failure

17

iv

related to acetaminophen overdose (SAF-O)

2.7.9 Types of acetaminophen poisoning

2.7.9(a) Repeated supra-therapeutic ingestion (RSTI) or

accidental staggered overdose

18

2.7.9(b) Suicidal or single time point overdose 19

2.8 Case reports and case series of acetaminophen poisoning

2.8.1 Acetaminophen poisoning in infants and children 19

2.8.2 Acetaminophen poisoning during pregnancy 21

2.8.3 Acetaminophen poisoning in alcoholic patients 22

2.8.4 Acetaminophen poisoning in teenagers and adults 22

2.8.5 Fatal cases of acetaminophen poisoning 23

2.9 Regulations to control sale and label of acetaminophen 24

2.10 Practices of consumers towards safe use of OTC medicinal

products

25

2.11 Practices of consumers towards safe use of acetaminophen

products

29

2.12 Perceptions of consumers towards safe use of OTC medicinal

products

30

2.13 Perceptions of consumers towards safe use of acetaminophen

products

31

2.14 Knowledge of consumers towards safe use of OTC medicinal

products

31

2.15 Knowledge of consumers towards safe use of acetaminophen

products

33

2.16 Reasons for using over-the-counter (OTC) drugs 34

2.17 Use of over-the-counter drugs and educational interventions 34

CHAPTER 3 : METHODOLOGY

3.1 Study design 36

3.2 Study population and sampling method 37

3.3 Inclusion criteria 38

3.4 Exclusion criteria 39

3.5 Data collection

3.5.1 Phase I study: quantitative structured survey 39

3.5.2 Phase II study: qualitative semi-structured interview 42

3.6 Data analysis

3.6.1 Data analysis for Phase I study 43

3.6.2 Data analysis for Phase II study 44

3.7 Ethics considerations 45

CHAPTER 4: RESULTS

4.1 Results for cross-sectional quantitative survey (Part I study)

4.1.1 Demographic and practice characteristics 46

4.1.2 Consumers’ practices of acetaminophen in Penang, Malaysia 47

4.1.3 Consumers’ total daily consumption of acetaminophen 500

mg tablet in Penang, Malaysia

55

4.1.4 Differences in the consumers’ practices of acetaminophen

(500 mg) in Penang, Malaysia based on demographic

characteristics

55

4.1.5 Consumers’ total daily consumption of acetaminophen 650 59

v

mg tablet in Penang, Malaysia

4.1.6 Differences in the consumers’ practices of acetaminophen

(650 mg) in Penang, Malaysia based on demographic

Characteristics

59

4.1.7 Consumers’ perception of acetaminophen in Penang,

Malaysia

63

4.1.8 Malaysian consumers’ total score of perception about use of

Acetaminophen

65

4.1.9 Differences in the consumers’ total score of perception

about use of acetaminophen in Penang, Malaysia based on

demographic characteristics

65

4.1.10 Consumers’ knowledge of acetaminophen in Penang,

Malaysia

69

4.1.11 Malaysian Consumers’ total score of knowledge about use

of acetaminophen

75

4.1.12 Differences in consumers’ total score of knowledge about

use of acetaminophen in Penang, Malaysia based on

demographic characteristics

75

4.2 Results of qualitative semi-structured interview (Part II study)

4.2.1 Demographic and practices characteristics 77

4.2.2 Thematic content analysis results 78

CHAPTER 5: DISCUSSIONS

5.1 Results for the quantitative structured survey 98

5.2 Results for qualitative semi-structured interview 104

CHAPTER 6: CONCLUSIONS AND RECOMMENDATIONS

6.1 Conclusion 108

6.2 Recommendations to improve the current practice 108

6.3 Study limitations 110

References 112

Appendices 131

vi

LIST OF TABLES

Page

Table 4.1 Demographic and practice characteristics of the

surveyed consumers

46

Table 4.2 Consumers’ practices of acetaminophen in Penang,

Malaysia

49

Table 4.3 Consumers’ total daily consumption of acetaminophen

500 mg tablet in Penang, Malaysia

55

Table 4.4 Differences in the consumers’ total daily consumption

of acetaminophen 500 mg tablet in Penang, Malaysia

based on demographic characteristics

57

Table 4.5 Consumers’ total daily consumption of acetaminophen

650 mg tablet in Penang, Malaysia

59

Table 4.6 Differences in the consumers’ total daily consumption

of acetaminophen 650 mg tablet in Penang, Malaysia

based on demographic characteristics

61

Table 4.7 Consumers’ perception of acetaminophen in Penang,

Malaysia

64

Table 4.8 Malaysian consumers’ total score of perception about

use of acetaminophen

65

Table 4.9 Differences in the consumers total score of perception

about use of acetaminophen in Penang, Malaysia based

on demographic characteristics

67

Table 4.10 Consumers’ knowledge of acetaminophen in Penang,

Malaysia

71

Table 4.11 Malaysian consumers’ total score of knowledge about

use of acetaminophen

75

Table 4.12 Differences in the consumers’ total score of knowledge

about use of acetaminophen in Penang, Malaysia based

on demographic characteristics

76

Table 4.13 Demographic and characteristics of the responding

consumers

77

vii

Table 4.14 Summary of the main themes and subthemes in the

qualitative study on the practices, perceptions and

knowledge

about the use of acetaminophen (paracetamol) among

the fourteen consumers in Penang, Malaysia

90

viii

LIST OF ABBREVIATIONS

AC Activated charcoal

ALF Acute liver failure

ALT Alanine aminotransferase

AMDI Advance Medical and Dental Institute

AOR Adjusted odd ratio

AP Alkaline phosphate

APAP Acetaminophen

AST Aspartate aminotransferase

ATN Acute tubular necrosis

BM Bahasa Malaysia (National language of Malaysia)

BUN Blood urea nitrogen

CI Confidence interval

Cr Creatinine

CYP2E1 Cytochrome P450 2E1

CMV Cytomegalovirus

CF Cystic Fibrosis

EBV Epstein-Barr Virus

FDA Food and Drug Administration

FHF Fulminant hepatic failure

GIT Gastrointestinal tract

HINTs Health Information National Trend Survey

HIV Human immunodeficiency virus

ICU Intensive care unit

IV NAC Intravenous N-acetylcysteine

INR International normalized ratio

KCHC King’s College Hospital criteria

LDH Lactic acid dehydrogenase

MOH Ministry of Health Malaysia

MRI Magnetic resonance imaging

NAC N-acetylcysteine

NAPQI N-acetyl-p-benzoquinone imine

ix

NPDs Non-prescription drugs

NSAIDs Non-steroidal Anti-inflammatory Drugs

OA Osteoarthritis

OR Odd ratio

OTC Over-the-counter

PT Prothrombin time

PTT Partial thromboplastin time

RA Rheumatoid arthritis

RR Relative Risk

RSTI Repeated supra-therapeutic ingestion

SAC Superactivated charcoal

SAF-M Severe acute liver failure related to therapeutic misadventure

SAF-O Severe acute liver failure in drug overdose

SD Standard deviation

SGOT Serum glutamic oxaloacetic transaminase

SGPT Serum glutamic pyruvic transaminase

SIRS Systematic Inflammatory Response Syndrome

SOFA Sequential Organ Failure Assessment

UK United Kingdom

URTI Upper respiratory tract infection

USM Universiti Sains Malaysia

US United State of America

x

LIST OF APPENDICES

Appendix A Questionnaire validation (reliability test)

Appendix B Questionnaire (Phase I quantitative survey)

Appendix C Informed written consent form (Phase I study)

Appendix D Interview guide (Phase II qualitative study)

Appendix E Informed written consent form (Phase II study)

Appendix F Examples of visual aids (product label)

Appendix G Examples of visual aids (package props)

Appendix H Ethnic approval letter

Appendix I Example of poster presentation

Appendix J Example of public talk about “know your medicine (acetaminophen)”

Appendix K Certificate of pre-viva presentation

Appendix L

Appendix M

Report of turnitin screening

Lists of publications and communications

xi

PENILAIAN AMALAN, PERSEPSI DAN PENGETAHUAN TENTANG

PENGGUNAAN ACETAMINOPHEN (PARACETAMOL) DALAM

KALANGAN PENGGUNA TEMPATAN DI PULAU PINANG, MALAYSIA

ABSTRAK

Acetaminophen (paracetamol) adalah ubat yang boleh dibeli di kaunter yang biasa

digunakan oleh pengguna-pengguna Malaysia sebagai swa-pengubatan untuk demam

panas dan sakit. Memandangkan peningkatan dalam kos perubatan adalah salah satu

cabaran kepada rakyat Malaysia, amalan swa-pengubatan dijangka akan terus

meningkat. Namun demikian, amalan swa-pengubatan tanpa maklumat dan

pengetahuan yang mencukupi boleh meningkatkan risiko keracunan acetaminophen.

Sesungguhnya, keracunan acetaminophen merupakan salah satu masalah sosial dalam

kalangan pengguna di Malaysia. Oleh itu, kajian ini dijalankan untuk menilai

penggunaan produk-produk acetaminophen dalam kalangan pengguna tempatan di

Pulau Pinang, Malaysia dari segi isu-isu berkaitan amalan, persepsi dan pengetahuan

mereka mengenai produk-produk tersebut. Kajian ini dibahagikan kepada dua

bahagian. Di bahagian pertama kajian ini, satu kaji selidik melalui penggunaan borang

soal selidik telah dijalankan di antara 400 orang pengguna di Pulau Pinang melalui

persampelan mudah. Bahagian kedua kajian ini adalah satu temu bual kualitatif

berstruktur separa yang dijalankan antara empat belas pengguna yang berumur antara

24 hingga 82 tahun dan tinggal di Pulau Pinang. Bahagian pertama kajian ini

menunjukkan bahawa produk-produk acetaminophen adalah popular dalam kalangan

pengguna. Semasa menilai jumlah pengambilan harian acetaminophen, 24.8 % dan

11.8 % daripada pengguna-pengguna tersebut masing-masing didapati telah terlebih

guna tablet acetaminophen 500 mg dan 650 mg. Majoriti pengguna memandang

acetaminophen sebagai satu ubat yang selamat untuk diguna (69.1 %) dan sangat

xii

berkesan untuk kesakitan yang ringan dan sederhana (81.8 %). Namun demikian,

kebanyakan daripada pengguna-pengguna tersebut didapati kurang berpengetahuan

terhadap dos, langkah berjaga-jaga semasa menggunakan acetaminophen, kesan-kesan

dan tanda-tanda bagi penggunaan acetaminophen secara berlebihan. Bahagian kedua

kajian ini menunjukkan bahawa pengguna-pengguna mempunyai sikap yang positif

terhadap acetaminophen dari segi populariti, keselamatan dan keberkesanan. Namun

demikian, mereka mempunyai kesukaran dalam membezakan antara produk-produk

generik yang terdapat di pasaran. Sesetengah pengguna menyatakan bahawa mereka

akan menggandakan dos atau mengambil dengan lebih kerap jika keadaan atau gejala

mereka berterusan selepas mengambil acetaminophen. Selain itu, label bagi

sesetengah produk acetaminophen didapati tidak menarik hati dan tidak mengandungi

maklumat yang mencukupi bagi pengguna-pengguna. Pengguna-pengguna tersebut

mencadangkan bahawa Kementerian Kesihatan Malaysia perlu menghasilkan kaedah

pendidikan yang berkenaan dengan penggunaan acetaminophen yang betul. Sebagai

kesimpulan, amalan, persepsi dan pengetahuan pengguna-pengguna mengenai

penggunaan acetaminophen perlu diperbaiki untuk memastikan penggunaan secara

berkualiti bagi produk-produk yang mengandungi acetaminophen.

xiii

AN EVALUATION ON THE PRACTICE, PERCEPTIONS AND

KNOWLEDGE ON THE USE OF ACETAMINOPHEN (PARACETAMOL)

AMONG THE LOCAL CONSUMERS IN PENANG, MALAYSIA

ABSTRACT

Acetaminophen (paracetamol) is an over-the-counter medicine commonly used by the

Malaysian consumers for self-medication of fever and pain. As increasing healthcare

costs is one of the challenge to Malaysians, the self-medication practice is expected to

increase. However, self-medication without proper information and knowledge could

increase risk of acetaminophen poisoning. Indeed, acetaminophen poisoning is one of

the social problems among the consumers in Malaysia. Hence, this study was

conducted to evaluate the use of acetaminophen products among the consumers in

Penang, Malaysia on the issues around their practices, perceptions and knowledge

about such products. This study was divided into two parts. In part I of the study, a

qualitative structured survey using a questionnaire was conducted among 400

consumers in Penang via convenient sampling. The second part of the study was a

qualitative semi-structured interview conducted among fourteen consumers aged

between 24 to 82 years old and living in Penang. Part I of the study revealed that

acetaminophen products were popular and usually used for fever and common pain

among consumers. About 24.8 % and 11.8 % of the consumers found to have over-

consumed the recommended maximum daily dose of acetaminophen 500 mg and 650

mg tablets respectively. The majority of consumers perceived acetaminophen as a safe

drug to use (69.1 %) and very effective for mild and moderate pain (81.8 %).

Nevertheless, most of the consumers had lack of knowledge regarding dosage and

precautions when consuming acetaminophen, and effects and signs of acetaminophen

over-consumption. The part II study showed that the consumers had a positive attitude

xiv

towards the popularity, safety and efficacy of acetaminophen. However, they had

difficulty in recognizing generic acetaminophen-containing products available in the

market. Some consumers claimed that they will double the acetaminophen dose or take

it more frequently if their conditions persisted. Besides, the product package label for

certain acetaminophen products were not attractive and informative enough for the

consumers. The consumers suggested that the Ministry of Health Malaysia should

established educational tools on the proper use of acetaminophen. In conclusion, the

consumers’ practices, perceptions and knowledge about use of acetaminophen need to

be improved in order to ensure the quality use of acetaminophen containing products.

1

CHAPTER 1

GENERAL INTRODUCTION

1.1 Introduction

Acetaminophen is a common constituent of over-the-counter (OTC)

analgesic and non-prescription medicine used to reduce fever and relieve general pain

such as headache, backache, toothache and menstrual pain. Besides, acetaminophen

combination products can use to treat cold and flu. In Malaysia, the OTC products can

be obtained easily from the supermarket, pharmacy, sundry shop, government

hospitals and clinics. Meanwhile, use of OTC products is popular among Malaysian

consumers (Ali et al., 2010). However, special attention is needed on the target

population included parents, caregivers, the elderly, pregnant women, students,

chronic alcohol drinkers, the adolescents and school-aged children who are at higher

risk of involve in drug poisoning (Gilbertson et al., 1996; Ecklund et al., 2001; Fawole

et al., 2001; Amoako et al., 2003; Bortolon et al., 2008; Crocetti et al., 2009; Du et al.,

2009; Ali et al., 2010; Dawood et al., 2010; Jensen et al., 2010; Klemenc-Ketis et al.,

2010; Albsoul-Younes et al., 2011; Almasdy et al., 2011; Dawood et al., 2011; El-Ezz

et al., 2011; Himmelstein et al., 2011; Chang et al., 2012; Chowdhury et al., 2012;

Corrêa Da Silva et al., 2012; Du et al., 2012; Fouladbakhsh et al., 2012; Anjan et al.,

2013; Baghianimoghadam et al.,2013; Garvey et al., 2013; Manchanda et al., 2013;

Abubakar et al., 2014; Almalak et al., 2014; Eldalo et al., 2014; Jensen et al., 2014;

Ayad et al., 2015; Gualano et al., 2015; Italia et al., 2015; Bohio et al., 2016). The

proper recommended dose of acetaminophen for adults is 500 mg to 1,000 mg every

4 to 6 hours, up to a total daily dose of 4000 mg and for infant or children is 15 mg/kg

every 4 to 6 hours, up to a total daily dose of 2400 mg (Madlen, 2010). An acute single

ingestion of acetaminophen greater than 10 g or 200 mg/kg (whichever is lower) in

2

adults or 200 mg/kg in children is considered hepatotoxic (Madlen, 2010). However,

acetaminophen toxicity can also occurred after repeated ingestion of supra-therapeutic

doses over a period of more than 8 hours (Madlen, 2010). These may lead to the

symptoms such as confusion, loss of appetite, stomach pain, nausea or vomiting. Liver

injury becomes evident when levels of aspartate aminotransferase (AST) and alanine

aminotransferase (ALT) begin to increase within 24 to 48 hours. This may eventually

lead to death (Schiødt et al., 1997; Dart et al., 2006a).

Currently, activated charcoal (AC) and N-acetylcysteine (NAC) is the

antidote for acetaminophen poisoning. AC helps to prevent absorption of drug in

bloodstream (Blakely and McDonald, 1995; Sato et al., 2003; Wananukul et al., 2010).

Meanwhile, NAC provides L-cysteine which is important to stimulate glutathione

synthesis (Waring et al., 2008a). Nevertheless, early initiation of AC and NAC therapy

respectively is essential as it is most effective for patients who are admitted to the

hospital within 1 to 2 hours (Brent, 1993; Lystbaek et al., 1995; Zed and Krenzelok,

1999; Christophersen et al., 2002; Wallace et al., 2002; Dart et al., 2006a;

GlaxoSmithKline, 2007; Daly et al., 2008; Thomason, 2012) and 8 to 10 hours (Yang

et al., 2009) of the acetaminophen ingestion. Besides, gastric lavage is effective at

reducing the absorption and increasing elimination of acetaminophen after the

overdoses and thus reducing the risks of liver injury (Dart et al., 2006a). Wendon et

al. suggested that gastric lavage is effective for patients who present within 1 to 6 hours

post ingestion (Wendon et al., 1995) while Lystbaek et al. recommended it to be given

between 2 to 4 hours after acetaminophen overdose (Lystbaek et al., 1995).

3

Acetaminophen poisoning is a common phenomenon around the globe. In

the United Kingdom, acetaminophen poisoning accounted for 48 % of hospital

admission and lead to 100 to 200 deaths yearly (Gunnell et al., 2000; Hawkins et al.,

2007). The data from the United States Poison Control Centres showed that there were

91 deaths out of 98,578 of all acetaminophen overdose cases in 2008 (Burda and Sigg,

2012) where the government spend US$87 million yearly to treat acetaminophen

poisoned patients (Mehrpour and Ballali-Mood, 2011). A study conducted at a general

hospital in Northern Malaysia found that acetaminophen poisoning accounted for

around 29 % of all drug poisoning incidents with 60 % of the cases were due to suicidal

and 33.3 % cases involved accidental ingestions. The majority (73.3 %) of the

acetaminophen poisoning cases involved patients aged between 16 to 30 years and 38

% of the cases involved ingestion dose of more than 10 gram (Mohd Zain et al., 2006).

Lack of health literacy is the main reason for poor knowledge and potential unsafe use

of acetaminophen-containing products (Shone et al., 2011). Besides, self-medication

without consultation of healthcare providers, which is a common practice among

consumers in Malaysia, could increase the risk of misuse and over-consumption of

acetaminophen (Almasdy and Sharrif, 2011). To overcome this problem, proper

labeling, educational interventions and public health activities may help to promote

proper use of acetaminophen (Shone et al., 2011).

1.2 Problem statement

In Malaysia, consumers are able to treat minor illness themselves due to easy

accessibility to over-the-counter (OTC) drugs including acetaminophen. However,

self-medication using acetaminophen without proper information and knowledge is

dangerous as this might leads to acetaminophen overdose and poisoning.

4

Acetaminophen poisoning is becoming an increasingly common social problem in

Malaysia and it involves consumers from various age groups. The poisoning requires

immediate emergency department visits and hospital admission and this places a

significant burden on healthcare costs. Indeed, the poisoning could leads to severe liver

injury and even death. Currently, little is known about the reasons behind the

acetaminophen poisoning among the Malaysian consumers. The consumers might be

unaware about the safe use of acetaminophen. However, currently there is no study

been carried out to evaluate the Malaysian consumers’ practices, perception and

knowledge of acetaminophen about its uses, dosage and toxicities.

1.3 Rational for the study

Currently, to the best of our knowledge, there are limited educational tools in Malaysia

to promote rational use of acetaminophen. Besides, little is known about the Malaysian

consumers’ practices, perceptions and knowledge of acetaminophen. An

understanding of consumers’ practices, perceptions and knowledge about use of

acetaminophen is important to the overall planning of educational interventions to

address the misuse of acetaminophen and subsequent poisoning. Therefore, this study

will provide baseline data to help in the development of educational tools on the proper

use of acetaminophen. Besides, the study findings will help the government agency or

private health institutions in designing educational interventions or programs for the

consumers with regards to the proper use of acetaminophen. This in return will

enhance the quality of acetaminophen use in achieving optimum health outcome for

the public.

5

1.4 General objectives

This study aimed to evaluate the practices, perceptions and knowledge of

acetaminophen among the consumers in Penang, Malaysia.

1.5 Specific objectives

1. To evaluate the differences in the consumers’ practices, perceptions and knowledge

of acetaminophen according to demographic characteristics.

2. To assess the risk factors for acetaminophen poisoning among the consumers

according to demographic characteristics.

3. To assess the consumers’ ability in differentiate between originator and generic

acetaminophen products.

The first and second specific objectives were achieved through both the phase I

(quantitative) and phase II (qualitative) study. Meanwhile, the third objective was

achieved by the phase II study.

1.6 Overview of thesis

Chapter 2, the literature review, starts with trends of acetaminophen use, epidemiology

of acetaminophen poisoning in Malaysia and overseas and also recommended and

toxic dose of acetaminophen in both adults and children.

The chapter continues with the prognosis, risk factors and clinical presentations of

acetaminophen poisoning. It is followed by the review of acetaminophen induced

fulminant hepatic failure (FHF), acetaminophen induced nephrotoxicity, King’s

College Hospital criteria versus Modified King’s College Hospital criteria for

determining mortality or requirement of liver transplantation, severe acute liver failure

6

related to therapeutic use of acetaminophen (SAF-M) versus severe acute liver failure

related to acetaminophen overdose (SAF-O) and accidental staggered overdose versus

single time point overdose. A review of previous case reports and case series of

acetaminophen poisoning cases in infants, children, pregnant women, alcoholic

patients, teenagers, young adults, middle aged and elderly people and fatal cases were

also included.

The chapter continues with the regulations to control sale and label of acetaminophen.

A review of the previous studies on consumers’ practices, perception and knowledge

about acetaminophen in overseas and Malaysia were also included in this chapter.

The methodology, results and discussion of the study are presented in chapter 3, 4 and

5 respectively. In chapter 6, conclusions and a set of recommendations to improve the

quality use of acetaminophen are provided.

7

CHAPTER 2

LITERATURE REVIEW

2.1 The use of over-the-counter (OTC) medicinal products among the

consumers

OTC medicinal products are widely used among the consumers around the globe. A

study in India showed that prevalence of self-medication using OTC drugs for fever

was observed among the University students (74 %) (Kumar et al., 2013). Besides, the

studies in Pakistan and Poland noticed that use of these drugs for headache were found

among the pregnant women (60 %) (Bohio at al., 2016) and secondary school students

(52 %) respectively (Pisarska et al., 2011).

A previous cross-sectional survey involved 481 female University students in

Malaysia revealed that the most common non-prescription drugs used by them were

pain killers & fever reducers (30.2 %), otolaryngology (ear, nose & throat) medicines

(10.8 %), health supplements (10.8 %), gastrointestinal disorders medications (8.5 %),

anti-infective agents (7.3 %) and traditional drugs (3.5 %) (Ali et al., 2010). Another

survey study in Malaysia involved 197 parents noticed that use of OTC drugs without

seeing a doctor were common among them in treating their children’s ailments

included pharyngitis (sore throat), pyrexia, cough and diarrhoea (Dawood et al., 2010).

2.2 The use of acetaminophen products among the consumers

Acetaminophen is one of the most popular OTC medicinal products among the

consumers in both developing and developed countries. Most consumers and

healthcare professionals had taken either acetaminophen-alone or acetaminophen-

combination products to treat menstrual pain (Tangchai et al., 2004; Chuamoor et al.,

8

2012; Tanmahasamut and Chawengsettakul, 2012), headache (Boardman et al., 2004;

Martínez Eizaguirre et al., 2006; Cuvellier et al., 2009), fever (Murphy, 1992; Linder

et al., 1999; Walsh et al., 2005; Walsh et al., 2007; Jensen et al., 2010; Trajanovska et

al., 2010; Oziegbe et al., 2011; Demir and Sekreter, 2012; Lava et al., 2012), dental

pain (Vogel et al., 2011) and common pain (Lucas et al., 2007; Trajanovska et al.,

2010; Kassaw and Wabe, 2012; Bello and Bello, 2013; Gonçalves et al., 2013).

Acetaminophen products were common among Nigerian secondary students due to its

efficacy, availability and affordability (Onohwosafe and Olaseha, 2004) whilst

Palestinian consumers were likely to purchase many strips of acetaminophen per

transaction and keep them in the house (Sweileh et al., 2004). In United States,

acetaminophen was the most common over-the-counter medications used among

children aged below 12 years old (Vernacchio et al., 2009) whilst the middle aged and

elderly people preferred to use combination of acetaminophen with hydrocodone and

propoxyphene to treat common pain (Blazer and Wu, 2009). Meanwhile, the children

in Switzerland were preferred to consume acetaminophen disintegrating tablets

(Ceschi et al., 2011). However, acetaminophen is less popular in some European

countries such as Finland since consumers preferred to use NSAIDs to treat chronic

pain (Pitkala et al., 2002; Breivik et al., 2006). A study in Bahrain showed that

acetaminophen products was the most common non-prescription pain killers used by

the consumers to treat headache, fever and pain due to the flu-like symptoms

(Mahmood Al-Qallaf, 2015).

9

Currently, there is lack of data on the use of acetaminophen among the Malaysian

consumers. Hence, surveys are needed to evaluate the issues around the use of

acetaminophen in both the public and private healthcare settings in Malaysia.

2.3 Epidemiology of acetaminophen poisoning in overseas

In United States, most acetaminophen poisoning cases were due to accidental or

staggered overdoses (70.4%) (Schiødt et al., 1997). Similar trend was observed in

Singapore where staggered overdose accounted for 68% of the acetaminophen

poisoning cases (Ng, K.C., 2003). However, staggered overdose only accounted for

24.3% and 15% of acetaminophen poisoning cases in the United Kingdom (Craig et

al., 2012) and Australia respectively (Sood et al., 2013). Acute acetaminophen

poisoning occurred mostly in younger adults (Hegazy et al., 2012; Schmidt, 2004;

Schmidt, 2005; Siddique and Patel, 2012) and females (Aakvik and Jacobsen, 2006;

Angalakuditi et al., 2008; Hegazy et al., 2012; Simkin et al., 2012; Sood et al., 2013),

with minimal involvement of children ( Hegazy et al., 2012; Sood et al., 2013). The

average age group of the patients involved in acetaminophen poisoning were found to

be within the range of 15 to 24 years (Schmidt, 2005) and 15 to 50 years (Sood et al.,

2013) according to findings from previous studies. Children and infants are at risk of

consuming acetaminophen accidentally while teenagers and adults are more prone to

suicidal poisoning (Amar and Schiff, 2007; Noshad et al., 2010; Olguín et al., 2011).

Acetaminophen poisoning accounted for 21 % in Norway (Aakvik and Jacobsen,

2006), 40 % in the United Kingdom (Gunnell et al., 2000; Vale, 2003; Hawkins et al.,

2007; Hewett et al., 2013) and 33 % in Singapore (Ponampalam et al., 2009) of all

hospital admissions due to poisoning. In United Kingdom, acetaminophen poisoning

10

accounts for more than 70,000 emergency hospital attendances and there were around

18 deaths per million populations yearly (Waring et al., 2008a). However, withdrawal

of co-poxamol (combination of acetaminophen and dextropropoxyphene) from the

market in United Kingdom has led to reduction in poisoning deaths in recent years

(Sandilands and Bateman, 2008; Hawton et al., 2009; Hawton et al., 2011; Hawton et

al., 2012; Thomason, 2012). Acetaminophen was responsible for over half of

deliberate self-poisoning cases among children and adolescents below 15 years who

were admitted to United Kingdom general hospitals (Hawton and Harriss, 2008).

Meanwhile, England and Wales had four times higher in mortality rate from

acetaminophen toxicities as compared to France (Gunnell et al., 1997; Morgan and

Majeed, 2005). In Oxford, acetaminophen was responsible for 50 % of acute kidney

injury cases (Lee, 2004; Amar and Schiff, 2007) and it caused 47 % of drug overdoses

(Mehrpour and Ballali-Mood, 2011).

There were 91 deaths out of 98,578 of all acetaminophen overdose cases according to

data from the United States Poison Control Centres in 2008 (Burda and Sigg, 2012).

The United States government spend US$87 million every year to treat acetaminophen

poisoned patients (Mehrpour and Ballali-Mood, 2011). Meanwhile, another study

from United States reported a reduction in yearly percentage of acetaminophen-related

acute liver failure from the year of 1998 to 2003 (Bataller, 2007)

2.4 Epidemiology of acetaminophen poisoning in Malaysia

In Malaysia, approximately half (51.5%) of the acetaminophen poisoning cases were

due to suicidal attempts (Fathelrahman et al., 2005). The poisoned cases occurred

mostly in females (about 70 %) (Fathelrahman et al., 2005; Mohd Zain et al., 2006;

11

Kaur et al., 2010), those who self-treatment with acetaminophen (69.7 %) (Kaur et al.,

2010) and unmarried people (54.4 %) (Kaur et al., 2010) The average age group of the

poisoned patients were found to be relatively young. A study by Kaur et al. found that

55.2% of the poisoned patients were aged between 16 to 25 years old (Kaur et al.,

2010). Another retrospective case review conducted in years 2000 to 2002 found

almost similar trend whereby 55.2% of the patients who involved in acetaminophen

poisoning were in the age group of 15.1 to 30 years old (Fathelrahman et al., 2005).

In this retrspective study, acetaminophen overdose accounted for 44.7% of all the 493

drug poisoning cases. For racial differences, Chinese made up 37.7 % of all cases,

followed by Indians (31.6 %) and Malays (26.6 %) (Fathelrahman et al., 2005).

Another retrospective case review involved 437 drug poisoning cases showed that

acetaminophen (44.6 %) was main causative agent of all cases. Besides, Indians

patients constituted 41.0 % of all cases, followed by the Malays (31.8 %) and Chinese

(20.5 %) (Kaur et al., 2010).

2.5 Recommended dose of acetaminophen in adults and children

The proper recommended dose of acetaminophen for adults is 500 mg to 1,000 mg

every 4 to 6 hours, up to a total daily dose of 4000 mg. For infant or children the

recommended dose is 15 mg/kg every 4 to 6 hours, up to a total daily dose of 2400 mg

(Madlen, 2010).

2.6 Toxic dose of acetaminophen in adults and children

An ingestion of 10 to 15 grams of acetaminophen may increase the risk of

hepatotoxicity (Prescott et al., 1974; McLean et al., 1976; Waring et al., 2008a; Tanaka

et al., 2000; Mehrpour and Ballali-Mood, 2011) while a 25 grams of acetaminophen

12

ingestion is considered as fatal (Schueler and Harper, 1995; Clark et al., 1973).

However, an ingestion of more than 3.25 grams of acetaminophen daily can increase

risk of liver injury among patients with osteoarthritis pain (Altman and Barthel, 2011).

A previous study found that an ingestion of 5 gram of acetaminophen had caused 17

% of death cases in Japan whilst the fatal cases in Western countries were due to

ingestion of 13 to 25 gram of acetaminophen. The fatal dose of acetaminophen was

low in the Japan study due to additional side effects of other active ingredients used in

acetaminophen combination products. Meanwhile, the Western countries consumers

preferred to use products which contain acetaminophen as the sole active ingredient

(Washio and Inoue, 1997).

2.7 Acetaminophen poisoning

2.7.1 Prognosis of acetaminophen poisoning

The overall mortality of acetaminophen toxicity is about 5 %. The international

normalized ratio (INR), pH and blood creatinine concentration are important

prognostic factors for predicting hepatotoxicity resulting from acetaminophen

poisoning (Vale, 2007). Liver injury occurred when prothrombin time (PT) is more

than 20 seconds at 24 hours after ingestion of acetaminophen. A peak PT of more than

180 seconds and blood pH of less than 7.3 is associated with survival rate of 8 % and

15 % respectively. Additionally, poor survival found to have related to increase of

serum creatinine for more than 300 µmol/litre (Vale, 2003). A study in the United

States reported 73 % of overall survival rate for patients with acute liver failure

(Bataller, 2007). Another study in United States revealed a 7.7 % of overall mortality

rate for 26,961 patients who experienced acetaminophen poisoning. There is also an

elevated mortality risk among patients with underlying liver diseases and heavy

13

drinkers (Kumar et al., 2011). Meanwhile, Mutimer et al. found that cerebral oedema

and sepsis were responsible for most of the acetaminophen mortality cases whilst the

rest was due to late treatment seeking, prolonged PT, coma, kidney injury and

metabolic acidosis (Mutimer et al., 1994).

2.7.2 Risk factors of acetaminophen poisoning

There were a few studies which revealed that repeated supra-therapeutic ingestion of

acetaminophen in heavy drinkers will induce CYP2E1 enzyme and deplete glutathione

store This in return will increased the accumulation of toxic substance N-acetyl-p-

benzoquinone (NAPQI) and thus increase risk of mortality after hepatotoxicity

(Lystbaek et al., 1995; Ho and Lam, 1996; Tanaka et al., 2000; Schmidt et al., 2002;

Manchanda et al., 2013). Besides, acetaminophen toxicity after massive overdose

usually occurred in patient who ingesting P450-inducing drugs such as rifampicin,

phenytoin, phenobarbitone and carbamazepine (Blakely and McDonald, 1995; Lane et

al., 2002). The use of St John’s Wort (Waring, 2012) and prolonged fasting were also

the risk factors for acetaminophen toxicity (Dart et al., 2006a). The use of tobacco with

acetaminophen will increase the oxidative metabolism of acetaminophen, elevation of

ALT and INR and eventually lead to liver injury (Schmidt and Dalhoff, 2003).

2.7.3 Clinical presentations of acetaminophen poisoning

Vomiting, nausea, abdominal pain, loss of appetite and confusion were common signs

of acetaminophen toxicity (GlaxoSmithKline, 2007). However, there are four stages

of clinical course of acetaminophen poisoning:

Stage I is occurred within 24 hours of acetaminophen ingestion. The patients may

experience nausea, vomiting, anorexia (Clark et al., 1973; Pajoumand et al., 2003;

14

Vale, 2003; Muñiz et al., 2004) abdominal pain (Vale, 2012; Muñiz et al., 2004) and

malaise (Pajoumand et al., 2003).

Stage II is an initial manifestations of liver toxicity which is occurs within 24 to 48

hours post ingestion (Muñiz et al., 2004). The clinical manifestations included

abdominal pain, increase of the AST, ALT, PT and bilirubin levels (Mehrpour and

Ballali-Mood, 2011; Pajoumand et al., 2003) and jaundice (Mehrpour and Ballali-

Mood, 2011).

Stage III is observed in 3 to 4 days after acetaminophen ingestion. The patients may

develop right upper quadrant abdominal pain, tenderness and hepatomegaly.

Proteinuria and haematuria may occur as well (Muñiz et al., 2004). There are also

elevations of PT, AST, ALT, bilirubin, BUN (Okeke and Okeibunor, 2010) and

ammonia levels (Vale, 2003; Muñiz et al., 2004). The patients may experience hepatic

necrosis (Pajoumand et al., 2003; Mehrpour and Ballali-Mood, 2011) and palpitation

(Clark et al., 1973).

Stage IV is taken place in 4 to 14 days after acetaminophen overdoses. The patient

may develop hepatic failure (Pajoumand et al., 2003; Vale, 2003; Muñiz et al., 2004)

or even fulminant hepatic failure (Clark et al., 1973; Mehrpour and Ballali-Mood,

2011). However, the patient may start to recover from the acetaminophen poisoning in

this state (Muñiz et al., 2004; Mehrpour and Ballali-Mood, 2011).

15

2.7.4 Acetaminophen induced hepatotoxicity and fulminant hepatic failure (FHF)

Acetaminophen induced hepatotoxicity is associated with production of the

intermediate NAPQI by liver cytochrome P450 system. It occurred when the

production of NAPQI is greater than the capacity to detoxify it, and the excess NAPQI

will bind to cellular components to cause the death of hepatocytes (Schiødt et al., 1997;

Dart et al., 2006a). This phenomenon of acetaminophen induced hepatotoxicity is also

referred as the raise of ALT or AST level greater than 1000 IU/L (Heubi et al., 1998;

Tsai et al., 2004; Prescott, 2005, Aakvik and Jacobsen, 2006; Gupta et al., 2009; Craig

et al., 2012; Varney et al., 2012) which may cause by history of exposure to multiple

dose of acetaminophen and increased risk in patients with hepatitis, cytomegalovirus,

Epstein-Barr virus and Wilson’s disease (Heubi et al., 1998).

Some patients developed FHF due to consume large amount of acetaminophen, late

treatment seeking and higher serum acetaminophen levels (Chan et al., 1996; Kanter,

2006). Regular alcohol consumption in excess of 21 units/week in males and 14

units/week in female, regular use of enzyme-inducing drugs such as rifampicin,

phenytoin, phenobarbitone and carbamazepine; conditions causing glutathione

depletion such as malnutrition, HIV infection, eating disorders and cystic fibrosis; and

ingestion of oral dose of 250 mg/kg to 350 mg/kg acetaminophen will increase the risk

of developing FHF in acetaminophen poisoned patients (Schueler and Harper, 1995;

Salgia and Kosnik, 1999; Wallace et al., 2002; Daly et al., 2008). The clinical

presentations of FHF included mental confusion, nausea, vomiting, anorexia, stomach

pain, jaundice, haematuria and metabolic acidosis (Lall and Paul, 1998; Dart et al.,

2006a). Prompt treatment is needed in FHF patients to prevent them from succumbing

to hepatic coma and death (Artnak and Wilkinson, 1998).

16

2.7.5 Acetaminophen induced nephrotoxicity

Acetaminophen induced nephrotoxicity is less commonly occurred than

acetaminophen induced hepatotoxicity. The overall incidence of acetaminophen

induced nephrotoxicity in patients with and without severe hepatic necrosis were 10 to

40 % and less than 2 % respectively. Besides, a previous study found that mild and

severe kidney failure among 45 acetaminophen poisoned patients aged 12 to 18 years

were 8.9 % and 2.2 % respectively. Acetaminophen induced nephrotoxicity had been

reported in patients with no evidence or mild liver injury and also patients who had

consumed large doses of acetaminophen with severe liver injury (Loh and

Ponampalam, 2006).

2.7.6 King’s College Hospital criteria for liver transplantation in patient with

FHF

Liver transplantation is required for acetaminophen poisoning patients who developed

severe liver failure. Acidosis, kidney failure, coagulopathy and encephalopathy are the

better factors in determining mortality or requirement of liver transplantation rather

than transaminases levels (Gupta et al., 2009). Additionally, arterial pH less than 7.3

after adequate fluid resuscitation, serum creatinine more than 300 µmol/L, INR more

than 6.5 and grade III-IV hepatic encephalopathy are criteria used by King’s College

Hospital for liver transplantation in the United Kingdom for the patients with FHF

(Schmidt and Larsen, 2006).

17

2.7.7 Modified King’s College Hospital criteria for liver transplantation in patient

with FHF

This criteria involved measurement of arterial lactate that exceeds 300 mmol/L after

adequate fluid resuscitation. Arterial lactate was confirmed as a prognostic marker in

acetaminophen-induced FHF. Arterial lactate is also correlated with Sequential Organ

Failure Assessment (SOFA) score and Systematic Inflammatory Response Syndrome

(SIRS) components. The SOFA scores included the conditions of respiratory failure,

thrombocytopenia and hypotension whilst SIRS components included temperature,

heart rate and white blood cell count. Death may occur when there is a high SOFA

score and high SIRS components (Schmidt and Larsen, 2006).

2.7.8 Severe acute liver failure related to therapeutic use of acetaminophen (SAF-

M) versus severe acute liver failure related to acetaminophen overdose (SAF-O)

SAF-M refers to hepatic injury appear after ingestion of more than 6 grams of

acetaminophen daily for 4 days and there are always occurred in consumers with high

alcohol consumption. Meanwhile, SAF-O refers to liver damage occur after excessive

intake of acetaminophen at single time period. Moreover, patients with SAF-M had

higher hepatotoxic dose, longer duration of acetaminophen use and increasing risk of

developing fulminant hepatic failure (FHF) as compared to those with SAF-O. The

SAF-M is as severe as SAF-O (Wartel et al., 2010).

18

2.7.9 Types of acetaminophen poisoning

2.7.9(a) Repeated supra-therapeutic ingestion (RSTI) or accidental staggered

overdose

Repeated supra-therapeutic ingestion (RSTI) is described as taking two or more high

dosage of acetaminophen in an interval of more than 8 hours until the total daily dosage

exceeded 4 grams in adults (Craig et al., 2012). Meanwhile, RSTI in children below 6

years old is referred as ingestion of 200, 150 or 100 mg/kg of acetaminophen in an

interval of over 24, 48 or 72 hours respectively (Dart et al., 2006b). Besides, the

ingestion of 200 or 150 mg/kg of acetaminophen in an interval exceed 24 or 48 hours

respectively is considered as RSTI in children above 6 years old (Dart et al., 2006b).

Acetaminophen toxicity has been reported after daily repeated ingestion of

acetaminophen for 2 to 8 days of 2000 mg in heavy alcohol drinkers, 4000 mg in

normal healthy adults and 60 to 150 mg/kg/day in children (Schiødt et al., 1997; Dart

et al., 2006a).

In United Kingdom, confusion about dosage of acetaminophen in liquid preparation

especially 500 mg/ml was common among parents and healthcare providers which

may lead to staggered overdose of acetaminophen (Aabideen et al., 2011). The RSTI

patients were usually older in age, chronic alcohol consumers, fasting, starving and

did not seek immediate treatment. They had increased risk of developing

hepatotoxicity, hepatic coma and acute tubular necrosis (Alhelail et al., 2011; Craig et

al., 2012; De-Giorgio et al., 2013). These patients normally had higher

aminotransferase levels than suicidal individuals and required admission to intensive

care unit (ICU) for further monitoring (Dargan and Jones, 2002; Gyamlani and Parikh,

2002). In the United States, a study reported that 23.7 % of these patients were at risk

19

of developing liver damage (Alhelail et al., 2011). Two other American studies showed

that rectal route of acetaminophen administration were more prone to RSTI as

compared to oral route (Losek, 2004). Besides, dental pain patient treated by

acetaminophen are at increased risk of RSTI (Vogel et al., 2011). An Australian study

revealed that for RSTI patients with low acetaminophen level and normal ALT and

AST level at any time, there is no risk of liver damage and prolonged NAC treatment

is not needed (Daly et al., 2008).

2.7.9(b) Suicidal or single time point overdose

Suicidal or single time point overdose refers to taking more than 4 grams of

acetaminophen at one time (up to 1 hour) (Schiødt et al., 1997; Dart et al., 2006a;

Waring, 2012). An ingestion of acetaminophen greater than 6 to 7 gram in adults or

200 mg/kg in children at a single time point is considered hepatotoxic (Schiødt et al.,

1997; Dart et al., 2006a). The suicidal overdose patient has higher serum

acetaminophen levels and they usually can be safely managed at medical wards rather

than in an ICU. This in return has helped the U.S government to save a cost of

US$500,000 yearly in managing the acetaminophen poisoning cases (Gyamlani et al.,

1999; Dargan and Jones, 2002; Gyamlani and Parikh, 2002).

2.8 Case reports and case series of acetaminophen poisoning

2.8.1 Acetaminophen poisoning in infants and children

Acetaminophen is commonly used for relieve pain and fever in infants and children. It

has an excellent safety profile in therapeutic doses. However, a study revealed that sick

children who aged less than 2 years old and received acetaminophen over 90

20

mg/kg/day for more than one day are at increased risk for development of liver injury

(Muñiz et al., 2004).

In a previous case report, a 58-day-old, 4.9 kg infant was given acetaminophen 80 mg

6 hourly for two days for her fever by her parent. She was subsequently admitted to

hospital with clinical presentation of dry mucous membrane, sunken eyes and

respiratory depression. The laboratory findings showed an AP level of 352 IU/L, AST

of 1070 IU/L, ALT of 490 IU/L, INR of 3.4, PT of 37.6 seconds and serum

acetaminophen level was 287 µg/mL. She was intubated due to her decreasing

respiratory function and was admitted to paediatric intensive care unit. She was treated

with 72 hours oral NAC regime and was discharged after 10 days (Muñiz et al., 2004).

One study demonstrated that younger children have less toxic metabolite (NAPQI)

produced by the P-450 system. Additionally, children are able to clear drugs more

efficiently because their livers compose a larger percentage of body weight compared

to adults (Bryant et al., 2003). Therefore, chronic liver injury found to be seldom

occurred in children after acute single accidental overdose of acetaminophen. (Daly et

al., 2008). For instance, in a previous case report, a 15 months old girl was presented

to hospital after accidental ingestion of 10 to 12500 mg acetaminophen tablets. She

was given 8 gram of activated charcoal at 1 hour post ingestion. The serum

acetaminophen level at 4 hours post ingestion was 525.9 µg/mL and a 72 hours oral

NAC treatment was given to her. She did not develop liver injury and was discharged

with stable condition (Bryant et al., 2003).

21

In another case report, a premature baby born at 25.5 weeks gestation had accidentally

received 420 mg of acetaminophen via IV infusion due to medication error. Ninety

minutes following the discovery of the acetaminophen overdose, a 20 hours IV NAC

treatment was initiated. The serum level at 5 hours post overdose was 180 mg/L and

there was no raised in liver enzymes, bilirubin and PT (Porta et al., 2012).

2.8.2 Acetaminophen poisoning during pregnancy

Acetaminophen is a popular and safe drug to be used in pregnancy. However, it is the

most commonly reported agents among drug overdose cases during pregnancy.

Unintentional acetaminophen poisoning can cause morbidity in pregnant women and

there is a need to educate them about the risk of acetaminophen overdose (Thornton

and Minns, 2012).

In a previous case report, a 22 years old pregnant woman was admitted to the hospital

with stomach pain and signs of liver damage. Before admission, she had taken 8 to 9

grams of acetaminophen daily for 10 to 14 days for her toothache. She developed FHF

and a liver transplantation was successfully done. However, intrauterine fetal demise

was occurred at two weeks after the liver transplantation. An MRI of the fetus showed

extensive peri-cerebral and intraventricular haemorrhage with extensive

periventricular leukomalacia (Thornton and Minns, 2012).

In another case report, a 25 years old pregnant woman was admitted to the hospital

with 35 grams of acetaminophen overdose and 37 units of alcohol. She had recently

split with her partner and this was her first and unplanned pregnancy. The patient was

recovered after treated with IV NAC (Shah and Karlapudi, 2009).

22

2.8.3 Acetaminophen poisoning in alcoholic patients

Repeated supra-therapeutic ingestion of acetaminophen can leads to liver toxicity in

chronic alcoholic patient. Alcoholics caused deficient in selenium, vitamin E and zinc

and subsequently faster the liver injury process (Schueler and Harper, 1995). There

was a case of a 34 year old chronic alcoholic male who ingested 12 extra-strength

acetaminophen tablets daily for pain and up to 18 tablets within 3 days. Besides, he

was consuming ibuprofen. The patient experienced nausea, vomiting and had dark

brown acid urine. His serum acetaminophen level was 34.7 µg/mL and there were

elevation of AST, ALT, PT, AP, and bilirubin whereas the albumin level was

decreased. He received oral NAC treatment and was discharged after 8 days. (Schueler

and Harper, 1995).

2.8.4 Acetaminophen poisoning in teenager and adults

Kavalci et al. reported a 16 years old female who had taken 8 grams of acetaminophen

for suicidal attempts. Upon arrival in hospital, she received IV NAC treatment and

later discharged with stable condition (Kavalci et al., 2009). Another case report by

Kojima et al. showed a 32 years old woman who had ingested 3 gram of

acetaminophen daily for several days. She presented to hospital with severe stomach

pain. Upon examination, there were increased in liver enzymes, hypokalaemia,

hypophosphatemia and low blood urea nitrogen (Okeke and Okeibunor, 2010). The

ingestion of acetaminophen was stopped and all the clinical signs and symptoms of

poisoning were resolved (Kojima et al., 2006).

Acetaminophen poisoning cases were also found among middle aged adults. Mazer

and Perrone reported a 47 years old woman who had ingested 9 grams of

23

acetaminophen daily for two days. She developed hepatotoxicity and was treated with

oral NAC. Her liver function eventually improved after the treatment and she did not

need liver transplantation (Mazer and Perrone, 2008).

Zell-Kanter et al. reported a 59 years old female who had serum acetaminophen level

of 1141 mg/L upon admission and she was started with IV NAC management. There

was an elevation of liver enzymes and creatinine phosphokinase as well. The patient

was fully recovery after the IV NAC treatment despite the high serum acetaminophen

level (Zell-Kanter et al., 2013).

2.8.5 Fatal cases of acetaminophen poisoning

Fatal cases of acetaminophen poisoning were reported for both high dose acute

ingestion and repeated-supra therapeutic dose ingestion. Maclean et al. reported a case

of a 40 years old man who ingested 60 tablets of acetaminophen (60 gram). He

experienced jaundice, vomiting, dilated pupils, enlarged liver, sinus tachycardia,

hypotension, dark brown acid urine and coma for 5 days. Gastric lavage was performed

at 7 hours after ingestion. Nevertheless, his clinical condition deteriorated and died at

10 hours after admission due to cerebral oedema and intense gastrointestinal

haemorrhage (Maclean et al., 1968).

There was a case report of a 29 years old woman who consumed 36 gram of

acetaminophen. The patient had chronically abused alcohol and diazepam, and

presented with history of emotional instability. Upon hospital admission, her serum

acetaminophen level was 160 µg/mL and she experienced hypotension,

hypoglycaemia and metabolic acidosis. Gastric lavage was performed and she was

24

given activated charcoal to treat the acetaminophen poisoning. Additionally, her serum

acetaminophen level at 12 and 36 hours were the same (100 µg/mL). She had

experienced impaired acetaminophen liver clearance with a half-life of acetaminophen

of more than 16 hours. Furthermore, there were elevation of PT, bilirubin, SGOT and

LDH level. The patient subsequently experienced second episode of hypoglycaemia

and died due to massive centrizontal liver necrosis, acute tubular necrosis and

pulmonary oedema (Zabrodski and Schnurr, 1984).

Zabrodski and Schnurr reported a fatal case which involved a 48 years old woman who

ingested 3.25 gram of acetaminophen daily for 3 weeks. The patient was a chronic

smoker with bronchitis and peptic ulcer and had 23 years history of chronic back pain

with misuse of pain killers. Upon hospital admission, she was presented with slurred

speech and complained of both back and stomach pain. Her initial serum

acetaminophen level was 300 µg/mL and she experienced hypoglycaemia. Gastric

lavage, activated charcoal and NAC were given for her acute acetaminophen

poisoning. The patient’s acetaminophen level was 220 µmg/mL at 12 hours and 183

µg/mL at 24 hours indicating that these levels were in toxic range. After 36 hours, she

had second episode of hypoglycaemia and died due to massive hepatocellular necrosis

(Zabrodski and Schnurr, 1984).

2.9 Regulations to control sale and label of acetaminophen

As there is a raise in the cases of acetaminophen poisoning, the US FDA has requested

drug companies to control the amount of acetaminophen in prescription products

(Martinez et al., 2012). Besides, the policy to control sale of acetaminophen has been

implemented by several countries in order to decrease suicide rates and self-poisoning